There is a clear need for guiding biopsy procedures, especially for epithelial dysplasia and early cancer that commonly arise focally within large tissue areas and cannot be identified by the naked eye. Endoscopic optical microscopy technologies are promising candidates for such image-guided biopsy as they provide information that is similar to that used by pathologists for the current standard of care. Unfortunately, as currently configured, these microscopies have small fields of view and are "point sampling" methods, making them unsuitable for the large area imaging required for biopsy guidance. We have developed a reflectance confocal microscopy technique, termed SECM that solves this problem by acquiring microscopic image data at very high speeds to automatically and comprehensively screen extremely large tissue areas. In addition, we have developed a laser method for marking locations on the tissue that correspond to images of interest identified by SECM. Taken together, these technologies provide a foundation for a new image-guided biopsy platform that is based on microscopic morphologic information. In this proposal, we will take this technology from the bench to the bedside by fabricating an endoscopic probe that incorporates these technologies and by testing its capability to guide biopsy in a cohort of 20 patients. Due to the considerable need for better methods to diagnose Barrett's esophagus (BE) and our expertise in esophageal imaging, the clinical focus of this grant will be the development of a device for improving surveillance of BE patients. While targeted to reduce the mortality of esophageal adenocarcinoma, this technology will also serve as a platform for large-area microscopic screening in other organ systems, such as the colon, lung, and bladder, where screening large tissue areas for dysplasia and early cancer is not well served by existing diagnostic paradigms. PUBLIC HEALTH RELEVANCE: This proposal will develop a biopsy guidance system based on microscopic images obtained over large epithelial surfaces. Using this device, we will determine the safety and feasibility of microscopic image guided biopsy in a cohort of 20 patients with Barrett's esophagus.